Bile acids are major excretory products of the liver and are the prime motive force in the generation of bile flow. At birth, bile secretion is decreased. The clincal consequences of this period of "physiologic cholestasis" are decreased excretion of other organic anions such as bilirubin and certain drugs, impaired fat digestion, and possibly an increased susceptibility to congenital and acquired liver disease. We have previously determined that serum cholate conjugates are markedly elevated in normal infants and in rat pups suggesting impaired hepatocellular transport of bile acids. Therefore, the objective of may researhc is to test the hypotheses that: 1) this immaturity of hepatic excretory function is related to impaired uptake and secretion of bile acids by the hepatocyte; that 2) maturation of bile acid transport is related to changes in the physical and chemical properties of the liver plasma membrane; and that; 3) post-natal diet, the endocrine milieu, and an increasing bile acid pool size may mediate the development of heptatic bile acid transport. To further delineate the normal development of hepatic bile acid transport in the human infant we will study the plasma clearance of a stable isotope of cholate in infants during the first year of life. We will determine taurocholate uptake and efflux by hepatocytes isolated from fetal, suckling, weanling and mature rats. Uptake of taurocholate will then be assessed apart from intracellular metabolism in vesicles prepared from rat liver plasma membrane. Transport data will be correlated with postnatal changes in plasma membrane lipid content, lipid microviscosity (determined by fluorescent polarization), and Na+ K+ ATPase activity and number of enzyme units. We will selectively manipulate diet, thyroid hormone, corticosterone, and bile acid pool size in an effort to prematurely induce or retard our previously defined changes in plasma membrane composition and in transport. These studies will pinpoint key features which limit bile acid transport and hence bile flow by the immature liver.